Severe ME Day of Understanding and Remembrance: Aug. 8, 2017
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PDK inhibitors

Discussion in 'General Treatment' started by AdamS, May 8, 2017.

  1. AdamS

    AdamS Senior Member

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    After reading the below abstract about the PDK4 inhibitor Diisopropylamine Dichloroacetate, I got excited again about PDK inhibitors. I have a few questions:
    • Are there any PDK inhibitors we can test out or is safety/availability a problem?
    • Do you think that PDK inhibitors could help improve symptoms in ME patients? If not, why?
    I've listed a few PDK inhibitors, I couldn't find many initially but will add to the list when I have more time.

    PDK1

    PDK2
    • ??
    PDK4

    Thanks, Adam
     
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  2. Jesse2233

    Jesse2233 Senior Member

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    I believe DCA is available OTC
     
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  3. Tunguska

    Tunguska Senior Member

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    This study combined two of the ones you listed, and they synergized: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551558/
    Similarly it's the combinations with other protocols I'm interested in trying, rather than PDK inhibitors alone. Get them to complement each other. The way I see it PDK inhibitors can make sense to into any scenario if used right.

    There's conflicting information about the other forms of butyrate, but in this one, Sodium Butyrate also had desirable effects (but in other studies it increased PDK instead - so I'm not certain about this one): https://www.ncbi.nlm.nih.gov/pubmed/28123081
    I don't know if this going through mTor or not.

    There's something to the Erk pathway and epidermal growth factor: https://www.ncbi.nlm.nih.gov/pubmed/21852536 but I haven't read this

    There was also stuff in the Fluge & Mella thread but I completely forgot. I wasn't as interested at the time. I'm kind of tired so if I misinterpreted something please point it out.
     
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  4. junkcrap50

    junkcrap50 Senior Member

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    That paper about the H1N1 mice and DCA inhibiting PDK, as well as a couple other papers by the same authors , are incredibly interesting. And I believe deserve more review by the community here than were giving in the Fluge & Mella PDH thread.
     
  5. Tunguska

    Tunguska Senior Member

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    I skimmed through your article (nice find by the way):
    Edit: Ah wait it was posted here: http://forums.phoenixrising.me/inde...-encephalopathy-cfs.48446/page-20#post-802851
     
    Last edited: May 8, 2017
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  6. alex3619

    alex3619 Senior Member

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    I would like to know if there are any patients here who have already tried these or similar treatments, and what the outcomes were.
     
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  7. Jesse2233

    Jesse2233 Senior Member

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    From a PR member who tried DCA back in 2014:
    @Hip and his friend tried it as well
     
    Last edited: May 8, 2017
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  8. AdamS

    AdamS Senior Member

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    @Tunguska Thanks for posting this...

    Just ordered some Vit B15/Pangamic Acid...will let you know how I get on. Not expecting anything but will try anything really.
     
    Last edited: May 9, 2017
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  9. Tunguska

    Tunguska Senior Member

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    Yeah my first thought was "great this might be accessible" but then I remembered pangamic acid supplements have a terrible reputation: https://en.wikipedia.org/wiki/Pangamic_acid
    He wrote me he didn't plan on trying it again for the time being... kinda speaks for itself... I'm scared of trying DCA because I've had neuropathy before of the worst kind, and DCA is super expensive. But DADA sounds alright, assuming you can get the real thing.

    I think the best results have been from super high-dose thiamine, a few posters, Lynn, Sidereal, etc. had great experiences with that, albeit temporary. But there are just as many if not more failures including me.
    http://forums.phoenixrising.me/inde...ent-story-focus-on-thiamine-deficiency.24059/
    The thread is titled "thiamine deficiency" but they were taking 1500mg+ so more than likely it's just the therapeutic effect(s), betting on PDH/PDK or something in glycolysis anyway. I'm not sure if it did anything for people's PEM though (this plays into my belief it might be more useful during activity although it should help a little anytime [but also that it may be better in combinations]).
     
    Last edited: May 9, 2017
  10. Tunguska

    Tunguska Senior Member

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    It's predictable, that if PI3K/Akt is significantly inhibited, that PDK inhibitors won't do much because glycolysis will have little substrate to work with, and worse because most will have some type of side effect or another, so all you get is the side effects with none of the benefits.

    I think some people might have to take an Akt and/or mTor activator in order for PDK inhibitor to work at all, or reliably. The exception would be those who already have high pyruvate levels, they probably don't need it at least not at first.

    It will also worsen ROS from mitochondria so that's a possible source of problems, and you might have to take a ROS scavenger like NAC, ALA or vit C.

    Point is I think if it doesn't work alone, I wouldn't give up right away.
     
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  11. Jesse2233

    Jesse2233 Senior Member

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    So if one has high pyruvate levels, a PDK inhibitor might work on its own?
     
  12. Tunguska

    Tunguska Senior Member

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    Yeah, I think it could work alone, at least temporarily.

    You might have other issues that would become limiting soon after starting though. (it's also not a guaranteed sign that Akt is working well, since it's a balance between production and consumption, rather than on/off)
     
  13. AdamS

    AdamS Senior Member

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    Do you know of any AKT/mTOR activators? Sure I read somewhere that aminos like Leucine/Glutamine can stimulate mTORC1, I took some Leucine last night actually, no idea if it helped though.
     
  14. Tunguska

    Tunguska Senior Member

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    A lot of the mTor activators in this thread http://forums.phoenixrising.me/index.php?threads/how-can-we-stimulate-mtor.49892/page-10#post-841424 also increase Akt, most of them afaik. These may already relieve PDH on their own to a certain degree through mechanisms that nandixon explained.

    Akt activators that don't increase mTorC1 are things like ALA and rapamycin, or more generally some of the AMPK activators but you have to look each of them up to see if they increase or lower Akt. (Akt also can relieve PDH a little on its own dep. on circumstance but I no longer think you can count on this)
     
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  15. Tunguska

    Tunguska Senior Member

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    Also the nitric oxide boosters often involve Akt, mTor and/or AMPK activation so they are good candidates to look at.
     
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  16. eljefe19

    eljefe19

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    @Tunguska I felt pretty sure I was improving 2-3 days into starting Rapamycin but I'm a week in now at 1mg and the last two days have been pretty standard PEM. Suffice to say I'm not feeling any tremendous relief from Akt activation. I shouldn't have by now shouldn't I? I've now tried several Akt activators without any great results.
     
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  17. Tunguska

    Tunguska Senior Member

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    Maintaining Akt is a requirement for things to work, but it's not quite sufficient, that's what I've been coming to. It would be fast relief, yes. During periods of recovery - or most of the day - I lean heavily toward using Akt+/mTorC1+, which has some action toward inhibiting PDK on its own (see nandixon posts). To exploit Akt+/mTorC1- properly I think maybe you have no choice to add a separate PDK inhibitor (there could conceivably be yet something else I haven't found yet). That said, I'm not suggesting combining rapamycin with DCA, it sounds dangerous.

    I was hoping maybe rapamycin had a magic undocumented effect that inhibited PDK (disease-specific or not) separately, but that's wishful thinking.
     
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  18. AdamS

    AdamS Senior Member

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    I can't say i've had any noticable effect from any supplement or drug i've tried other than alcohol, even after 1-2 pints i'm almost normal again. In fact, i've managed nights out recently fueled by alcohol, it even pulled me out of a crash. There must be something in this...blunting B Cell secretion or microglial activity, it's not a long term solution because hangovers suck but nice instant relief nonetheless. Naviaux talks about personalised treatment based on metabolomics, I wonder if this translate to symptomatic relief or just make the tests look better? Perhaps ME does take a long time to recover from, even with the right treatment, this is certainly the case from most Valcyte/Rituximab stories. I'm desperate to find something that we can try (as we all are), i'm gutted Rapamycin didn't work out for you @eljefe19 as that seemed to show promise!
     
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  19. Jesse2233

    Jesse2233 Senior Member

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    Likewise, though maybe it requires a somewhat longer trial
     
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  20. Tunguska

    Tunguska Senior Member

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    Do you try combinations much? There are almost no supplements that work alone on me except opioids and ALA and it's only to a degree.

    Dr. Davis expects a solution that targets the blood factor to be a single drug, but nothing that I'm talking about is targeting that blood factor; so conversely I expect all these things we're looking at to work [best] in combinations.

    @eljefe19 Remember there might be a disconnect between the short-term relief and the disease-modifying aspects if rapamycin has any which might occur after longer time, unfortunately there's absolutely no evidence for it, so who knows. I would agree that Akt activation alone is not helping you, but who knows what else the drug is doing or not doing. There's also that question of how much you're actually absorbing (see comment on the rapamycin thread).
     
    Last edited: May 9, 2017
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